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Evidence That Hyperconjugative Interactions Are Not Responsible Or ARTICLES PUBLISHED ONLINE: 4 JULY 2010 | DOI: 10.1038/NCHEM.721 Computational evidence that hyperconjugative interactions are not responsible for the anomeric effect Yirong Mo* The ‘anomeric effect’ is the thermodynamic preference for polar substituents to occupy the axial position in the chair conformation of various heterocycles. The most common explanation given for this effect at present is hyperconjugation from the lone pairs on the ring heteroatom to the antibonding orbital between the anomeric carbon and its linking substituent. Alternatively, the anomeric effect could be explained by intramolecular electrostatic interactions between local dipoles. Few models can provide convincing data for either theory at the quantum-mechanical level. Now, using the extended block-localized wavefunction method, which is the simplest form of valence bond theory, we have evaluated the degree of hyperconjugation in various compounds that display the anomeric effect and have interpreted their conformational preferences in terms of steric, hyperconjugation and dispersion effects. The results provide strong evidence that hyperconjugative interactions are not responsible for the anomeric effect and that it is better interpreted in terms of electrostatic interactions. he ‘anomeric effect’ is a stereoelectronic effect that was discov- bond14. However, this has been refuted by Perrin and colleagues, ered by Edward1 in 1955 while studying carbohydrates; the who showed that the electrostatic model can rationalize the geo- Tterm was later coined by Lemieux and Chu¨2 in 1958. It metrical variations at least in 2-methoxy-1,3-dimethylhexahydro- refers to the thermodynamic preference for electronegative (polar) pyrimidine15. Further refinements of this electrostatic model ... 16 substituents bonded to C1 (the anomeric carbon shown in Fig. 1 include the consideration of favourable C2H O hydrogen bonds . in a substituted tetrahydropyran) to take up an axial position (a- An alternative and popular rationalization of the anomeric effect anomer) rather than an equatorial position (b-anomer) in the is based on electron delocalization from the oxygen lone pairs to the 3 17 chair conformation of a monosaccharide . The anomeric centre is vacant antibonding orbital sCY* (Fig. 2b) . This kind of n s* critical to the reactivity of carbohydrates because it is the site at negative hyperconjugative interaction can explain the geometry which ring opening occurs, producing the important functional changes, because the electron delocalization increases the double- carbonyl group. The preference for the a-anomeric diastereomer bond character of the O2C1 bond but weakens the C12Y bond. increases as the electron-withdrawing capability of the anomeric sub- The hyperconjugation model, however, is inconsistent with the stitutent Y increases. When Y is a carbon atom substituent such as a reverse anomeric effect, where the equatorial conformation is pre- methyl group, however, the b-anomer is favoured so that steric ferred5,18, and some researchers have questioned the validity of the repulsions between the ring and the substituent are minimized. n s* hyperconjugation model16,19. A compromise that takes into Although the anomeric effect was initially found in carbo- account such different views is that both the dipole–dipole and hydrates and ubiquitously exists in monosaccharides and their hyperconjugative interactions contribute to the anomeric effect18. derivatives, the concept has now been generalized to saturated Although extensive computational studies have correctly heterocycles and acyclic systems containing heteroatoms. Many described and predicted the conformational features of compounds experimental and theoretical studies have been conducted regarding exhibiting the anomeric effect, few have been able to differentiate the understanding and utilization of this peculiar effect4–9, which various factors such as steric (Pauli exchange), electrostatic and elec- plays a central role in conformational analysis in modern organic tronic interactions at the quantum-mechanical level. Individual esti- chemistry10. mates of various interactions can provide deep insights into the The most intriguing issue surrounding the anomeric effect is why origin of the anomeric effect. Perrin and colleagues examined the it occurs. When Edward1 proposed the anomeric effect, he intui- change in the anomeric effect when the oxygen of an anomeric mol- tively linked it to the lone pairs on the ring oxygen. This idea ecule was replaced by nitrogen15. Owing to its lower electronegativ- later developed into the electrostatic model, which states that the ity when compared with oxygen, nitrogen would have weaker preference for the a-anomer arises from the favourable local electrostatic interactions and stronger hyperconjugative inter- dipole–dipole interaction, as illustrated in Fig. 2a (ref. 11). This elec- actions. The results revealed that the anomeric effect is weaker in trostatic model is in agreement with the experimental evidence, the nitrogen analogue and that 2-aminotetrahydropyran exhibits which suggests that aqueous solvation effects stabilize the b- the reverse anomeric effect20, suggesting that electrostatic inter- anomer and thus reduce anomeric stabilization in many systems actions predominate. However, the hyperconjugation model is greatly such as tetrahydropyranosyls12,13. It has also been claimed that the supported by direct computations of the n s*ands s* electrostatic model is unable to explain the variations in bond dis- stabilization energies based on the natural bond orbital (NBO) tances and angles around the anomeric carbon atom, such as the method21. It has been pointed out, however, that the NBO shortening of the O2C1 bond and the lengthening of the C12Y method tends to highly overestimate stabilizing electron Department of Chemistry, Western Michigan University, Kalamazoo, Michigan 49008, USA. *e-mail: [email protected] NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry 1 © 2010 Macmillan Publishers Limited. All rights reserved. ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.721 O O methods are computationally demanding due to the non-orthogon- Y C1 C1 ality of orbitals, the introduction of doubly occupied (a feature of molecular orbital (MO) theory) but strictly localized (a feature of Y VB theory) bond orbitals can significantly simplify the compu- tational process. Following this strategy, the wavefunction of an elec- Figure 1 | Anomeric effect in substituted tetrahydropyran. The anomeric tron-localized reference Lewis structure can be derived by effect refers to the preference for polar substituents to occupy the axial, partitioning the system into several mutually interacting subgroups rather than equatorial, position in a chair conformation. This is illustrated and restricting the expansion of each MO in only one subspace. All here with the thermodynamic equilibrium between a (right side) and b (left block-localized MOs are self-consistently optimized30–35. Our block- side) anomers of a substituted tetrahydropyran where Y is an localized wavefunction (BLW) method can not only decompose the electronegative substituent. intermolecular interaction energy into a few physically meaningful terms36, but can also probe the electron delocalization within a mol- O O ecule. Similar approaches have been successfully applied by others to 23,37–41 C C study conjugation and hyperconjugation effects . 1 1 In this work, we studied molecules that exemplify the anomeric Y Y effect, including dimethoxymethane and substituted tetrahydropyr- ans, as well as the reference molecules dimethyl ether, tetrahydro- ab pyrans and substituted cyclohexanes, which have no anomeric effect. The BLW method was applied to these systems to quantify Figure 2 | Two most common explanations for the anomeric effect. a,The the electron delocalization and steric effects and subsequently criti- electrostatic model states that the preference for the -anomer arises from a cally examine the role of hyperconjugative interactions in the favourable local dipole dipole interactions. b, The hyperconjugation model 2 anomeric effect. is based on the stabilization gained from electron delocalization from the oxygen lone pairs to the vacant antibonding orbital sCY*. Results delocalization energies (DEs) due to the non-optimization of bond Dimethoxymethane. Dimethoxymethane is the simplest example orbitals, as exemplified by the recent controversy over the nature of with which to illustrate the anomeric effect: its gauche the ethane rotation barrier22–26. conformation around the C2O bonds is more stable than the One plausible way by which to determine the impact of conjuga- trans conformation. Moreover, as there are two anomeric centres, tive and hyperconjugative electron delocalization is to use ab initio the most stable conformer, namely the gauche2gauche (GG) valence bond (VB) theory27,28, which can define wavefunctions for conformer shown in Fig. 3 (1a), is 3–5 kcal mol21 more stable individual resonance structures. Among all possible resonance than 1c the trans2trans (TT) conformer; this effect is about twice structures with electrons strictly localized on bonds or atoms, the as big as that in sugars. Dimethoxymethane has therefore been one with the lowest energy is taken as the reference to measure widely selected as the prototype for computational studies on the the electron delocalization effect29. Although ab initio VB anomeric effect19,42–44. a 1a − GG 1b − GT 1c − TT b 2a − α 2b
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